The goal of this research is to develop a proteomics approach to simultaneously quantify hundreds of proteins and their modifications in the postsynaptic density (PSD). PSD is a specialized membrane structure that is essential for neuronal communication, and dynamic protein changes in the PSD play a pivotal role in synapse plasticity. However, there is no method available to monitor the global protein changes in the structure under physiological and pathological conditions. Recently, we have made progress in developing novel mass spectrometry-based technologies to systematically identify protein elements in the PSD, and we propose to develop a quantitative approach for all proteins of interest. Basically, the approach will utilize an isotopic-labeled synthetic peptide for each protein. Hundreds of labeled peptides will be pooled together and serve as universal standards for PSD proteome. The strategy bypasses the requirement for antibodies and the measurements will be highly specific. In addition, the method provides absolute quantification of targeted proteins and protein modifications, enabling the stoichiometry analysis for protein complexes and protein modifications. This tool will allow quick evaluation of the PSD proteomic changes in various samples ranging from neuronal cell cultures to animal models of neurological disease and drug abuse.